1. Field of the Invention
The present disclosure relates to a novel N2,N4-bis(4-(piperazin-1-yl)phenyl)pyrimidin-2,4-diamine derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for the prevention or treatment of cancers, containing the same as an active ingredient.
2. Description of the Related Art
Unlike the normal cells which can perform regular and controlled growth and inhibition as necessary, cancer is a cell mass consisting of undifferentiated cells which ignore the states required inside tissues and unlimitedly proliferate and is also called tumor. The unlimitedly proliferating cancer cells invade into the neighboring tissues and, in serious cases, cause metastasis of cancer to other organs in the body thereby accompanying severe pains resulting in death.
According to the report of the American Cancer Society, more than 12 million people in the world were newly diagnosed of cancer in 2007 and 7.6 million people died of cancer, that is, about 20,000 people died of cancer every day. In Korea, according to the 2006 report of the Statistic Korea, the number one cause of death was cancer. Accordingly, there is an urgent need for the development of a tumor therapeutic agent with excellent therapeutic effect to ensure reduction in mental and physical pains due to occurrence of cancer and struggles with the cancer and improve the quality of life. Even with the numerous efforts, the exact mechanisms of how normal cells are transformed into cancer cells have not been clearly identified yet, but various factors such as extrinsic factors (for example, environmental factors, chemicals, radiations, and viruses), and intrinsic factors (for example, genetic factors and immunological factors) are complexly involved in the occurrence of cancer. The genes associated with the occurrence of cancer are oncogenes and tumor suppressor genes, and cancers occur when the balance therebetween is not maintained due to the extrinsic or intrinsic factors.
Cancers can be largely classified into a blood cancer and a solid cancer. Cancer can develop in almost all regions of the body including lung cancer, stomach cancer, breast cancer, liver cancer, uterine cancer, esophageal cancer, skin cancer, etc. For cancer treatments, a few target therapeutic agents such as Gleevec® or Herceptin® have been used for the treatment of certain cancers but most cancer treatments have been resorting to surgeries, radiation therapies, and chemical therapies which inhibit cancer cell proliferation. However, because the existing chemical therapies are not target-specific therapies, they had the side effects due to toxicities and the drug resistance, and their treatments often led to failure regardless of their initial success in treatments. Accordingly, in order to overcome the limits of the chemical therapies, there is a continued need for the development of a target-specific therapeutic agent with an exact anticancer mechanism.
As such, numerous studies have been focused on specific molecular biological factors associated with tumorigenesis for the development of the target-specific therapeutic agents. In particular, the molecular biological factors are widely used in cancer prognosis and determination of whether chemical therapies and radiation therapies should be used.
The most representative drug to inhibit the tyrosin kinase receptor of a specific molecular biological factor may be Gleevec®. Gleevec® which acts as an anticancer agent by inhibiting the activity of Bcr-Abl fusion gene formed by chromosomal translocation in Philadelphia chromosome observed in chronic myeloid leukemia patients and is a tyrosine kinase inhibitor, has been showing a satisfactory therapeutic effect when administered to the chronic myeloid leukemia patients. Examples of the drugs showing an anticancer effect as tyrosine kinase inhibitors include epidermal growth factor receptor (EGFR) used as a therapeutic agent for non-small cell lung cancer, gefitinib and erlotinib as tyrosine kinase inhibitors, and sorafenib and sunitinib as a therapeutic agent of renal cell carcinoma, but they are known to have side effects such as bleeding, heart attack, heart failure, and liver failure.
Recently, anaplastic lymphoma kinase (ALK) has been discovered in various tumors in human bodies and is thus being studied as a target product for target-specific treatments.
The tumorigenesis of ALK has been identified mostly by the study on the fusion gene of anaplastic lymphoma kinase-nucleophosmin (ALK-NPM) observed in anaplastic large cell lymphoma. Once ALK is activated by the gene fusion, the tyrosine kinase possessed by ALK starts to behave abnormally and induces cancer. That is, the abnormally activated ALK induces proliferation of cells, inhibits apoptosis to prevent programmed cell death and rearranges cell frames and changes the shape of cells. The oncogenic conversion of ALK occurs by the interaction with a downstream molecule which is a target material of ALK, wherein the downstream molecule is a material to mediate the intracellular signal transduction. ALK can be connected to other tyrosine kinases, either normal or oncogenically converted ones, and interact therewith, or activate other various kinds of pathways.
In particular, the ALK gene in lung cancer cells fuses with echinoderm microtubule-associated protein-like 4 (EML4) gene and produces EML4-ALK, which is an active form of tyrosine kinase. Here, the oncogenic capability of the EML4-ALK is known to be dependent on enzyme activity, and Mosse et al. have reported amplification of about 26% of the ALK gene in 491 neuroblastoma subjects. Additionally, the ALK gene is known to be expressed in many nonhematopoietic cell tumors such as large B-cell lymphoma, systemic histiocytosis, inflammatory myofibroblastic tumor, esophageal squamous cell carcinoma, non-small cell lung cancer, rhabdomyosarcoma, myofibroblastoma, breast cancer, and melanoma cell line. In the case of the rare disease called inflammatory myelofibroblast tumor, various kinds of ALK fusion proteins are frequently discovered and thus these fusion proteins are believed to be closely associated with the tumorigenesis.
Accordingly, therapeutic agents regarding the ALK-NPM for cancer treatment by blocking the activation pathway of ALK are being developed. Recently, Crizotinib® (PF-02341066), which is a drug developed by Pfizer as a selective inhibitor for tumorigenic mutation and is one of small molecule tyrosine kinase inhibitors, is known to be effective in the treatment of non-small cell lung cancer, and was approved as a new drug by the FDA in 2011.
Additionally, NVP-TAE684 and LDK-378 of Novartis and CH5424802 of Chugai are also known to be effective in reducing tumor size in neuroblastoma cell lines in addition to anaplastic large cell lymphoma.
WO 2009143389, WO 2008051547, WO 2004080980, WO 2012061415, WO 2009145856, US 2009/7589200, US 2009/7517886, and WO 2005016893 indicates that candidate therapeutic materials with various frames for use to inhibit the ALK activity are being developed, and that pyrimidine derivatives selectively inhibit ALK and thus can be developed as an anticancer agent. These compounds, although having both in vitro and in vivo activities, reportedly have problems such as deterioration in selectivity on different kinases such as insulin receptor and side effects in heart.
Meanwhile, activated Cdc42-associated kinase (ACK1), being a non-receptor tyrosine kinase, is a kind of growth-promoting tyrosine kinase gene. ACK1 can activate Cdc42, Rac, and FAK via various signal pathways, and is also known as a device for regulating endocytosis via clathrin.
Recently, active studies have been performed on the correlation between ACK1 and tumorigenesis and metastasis.
First, Mahajan, N. P. discovered that the activity of androgen receptor (AR) generates a castration-resistant prostate cancer, wherein ACK1 performs a phosphorylation with the androgen receptor to increase its activity thereby contributing to the occurrence of cancer (Cancer Res. Vol. 65, (2005) p. 10514; Proc. Natl. Acad. Sci. U.S.A. Vol. 104, (2007) p. 8438). Additionally, van der Horst, E. H. revealed that the overexpression of ACK1 improves the motility of cancer cell lines and invasion capabilities thereby promoting metastasis of cancer (Proc. natl. Acad. Sci. U.S.A. Vol. 1032, (2005) p. 15901). Above all, ACK1 performs a phosphorylation with WW domain containing oxidoreductase (Wwox), which is known to inhibit cancer cells, and the accompanying ubiquitination induces its progress to induce the decomposition of Wwox thereby promoting metastasis of cancer cells while preventing cancer treatment (Cancer Res. Vol. 65, (2005) p. 10514; Cancer res. Vol. 61, (2001) p. 8068).
Therefore, it is apparent that ACK1 is most highly associated with the occurrence and metastasis of cancer, and thus there is an urgent need for the study and development of ACK1 necessary for the prevention and treatment of cancer.
Accordingly, the present inventors, while endeavoring to develop a compound having the inhibitory effect against the ALK, discovered that a N2,N4-bis(4-(piperazin-1-yl)phenyl)pyrimidin-2,4-diamine derivative with a certain structure can act as an inhibitor of the activities of ALK and ACK1, and thereby completed the present invention.